Current Treatment Options in Gastroenterology (2014) 12:18–33 DOI 10.1007/s11938-013-0002-7

Esophagus (E Dellon, Section Editor)

New Approaches to Management of PPI-Refractory Gastroesophageal Reflux Disease Fehmi Ates, MD Michael F. Vaezi, MD, PhD, MSc* Address *Division of Gastroenterology, Hepatology, and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, C2104-MCN, Nashville, Tennessee, USA Email: [email protected]

Published online: 16 January 2014 * Springer Science+Business Media, LLC 2014

Keywords GERD

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Reflux disease

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Poor response

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Refractory

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Treatment

Opinion statement “Refractory GERD” is one the most common misnomers in the area of gastroesophageal reflux disease. The term implies reflux as the underlying etiology despite unresponsiveness to aggressive, often twice-daily proton pump inhibitor therapy. The term should be replaced with “refractory symptoms.” We must acknowledge that in many patients, symptoms of reflux often overlap with non-GERD causes such as gastroparesis, dyspepsia, hypersensitive esophagus, and functional disorders. Lack of response to aggressive acid suppressive therapy often leads to esophagogastroduodenoscopy followed by pH or impedance monitoring. In the majority of patients these tests are normal. The role of non-acid reflux measured by impedance pH testing in this group is uncertain at best and the results from this test alone should not be used to refer patients to surgical fundoplication. In patients unresponsive to acid suppressive therapy, reflux is most commonly not causal and a search for non-GERD causes must ensue.

Introductıon Gastroesophageal reflux disease (GERD) is a chronic condition that develops when the refux of stomach contents causes troublesome symptoms and/or complications [1]. Besides classical symptoms such as heartburn and regurgitation, other symptoms include chest pain, cough, asthma, and hoarseness. GERD is

very common, affecting 20 % of the US adult population weekly and 7 % daily [2]. It results in significant morbidity and considerable impairment of quality of life, such as permanent discomfort to the patient with repeated visits to the doctor, as well as high costs of exams and treatment [3]. The introduction of proton

New Approaches to Management of PPI-Refractory Gastroesophageal Reflux Disease pump inhibitors (PPIs) has had a significant positive impact in treating GERD. A substanital improvement in mucosal healing as well as symptom resolution is expected with this new class of drugs that is superior to that achieved by histamin-2 receptor antagonists (H2RA). Despite the high efficacy of PPIs, treatment of GERD fails in a proportion of patients. “PPI failure” has become a common clinical predicament. This PPIrefractory patient group constitutes a significant proportion of patients treated by general practitioners, internists, and gastroenterologists. In this review we will discuss newly accumulated information about the management of this difficult group of patients, with emphasis on diagnosis and treatment of other possible co-morbid conditions.

Definition of “refractory GERD” The term “refractory GERD” has traditionally been employed to define a heterogeneous group of patients with varying symptom presentation (frequency and severity), PPI dosing regimen (once or twice daily), and response to therapy (from partial to absent). There is no established consensus regarding the definition of “refractory GERD” [4]. The FDA has not approved the use of PPIs in dosages greater than once daily, even

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though higher doses are prescribed regularly in clinical practice. Thus, some investigators consider a failure to achieve satisfactory symptomatic response (e.g., less than 50 % improvement) to once-daily PPI to be classified as refractory disease. Other investigators consider inadequate response to twice-daily PPI treatment as refractory disease [5]. Because “refractory GERD” is a patient-driven phenomenon, PPIfailure patients who seek medical attention will exhibit different frequency and/or severity of symptoms with varying c ausal etiology [ 6]. It is important to recognize that the term “refractory GERD” is a misnomer, since it implies underlying GERD, which is not true in many patients. Thus, the term should be replaced by “refractory symptoms”. This term is more apt without suggesting reflux disease as the only potential link. One suggested reasonable definition may be ‘symptoms (heartburn and/or regurgitation) that are not responding (persistent symptoms at least 3 times per week) to a stable, double dose of a PPI during a treatment period of at least 12 weeks’ [7]. Thus, in the forthcoming discussion we will use the term “refractory symptoms”, which we believe better describes this group of patients.

Approach to refractory symptoms Symptom evaluation In clinical practice, diagnosis and subsequent treatment of patients depends on subjective reporting of a constellation of symptoms attributed to GERD, which in most cases may not be GERD-related. This may explain refractoriness to acid-suppressive therapy. Thus, a careful and detailed investigation of a patient’s complaints is key to identifying potential reasons for why patients do not respond PPI therapy [8]. Substernal burning is an important symptom attributed to GERD. In clinical trials of GERD, symptom questionnaires are often employed to diagnose GERD. However, many are neither sensitive or specific for reflux. The GerdQ questionnaire is a revision of the Reflux Disease Questionnaire (RDQ) that, in addition to having positive predictor questions about heartburn and regurgitation, includes negative predictors about epigastric pain and nausea [9]. It achieves a sensitivity of 65 % and specificity of 71 % for the diagnosis of GERD, similar to that achieved by the clinical judgement of gastroenterologists [10]. Re-analysis of data from two large, randomized trials involving acid-suppression therapy found that PPI was most effective in individuals with symptoms limited to ‘substernal burning’ [11]. Heartburn is characterized by a painful retrosternal burning sensation of fairly short duration (several minutes). It is also important to

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Esophagus (E Dellon, Section Editor) recognize that regurgitation, an important presentation in patients with GERD, may not respond to acid-suppressive therapy since it is due to volume reflux and mechanical defects of the reflux barriers. In clinical trials, the efficacy of PPIs for alleviation of regurgitation is considerably lower than for heartburn [12]. As a result, a patient with both heartburn and acid regurgitation may have sufficient relief of heartburn ‘on’ PPIs, but persisting regurgitation [13]. Thus, when faced with patients with refractory symptoms, it is essential to identify which symptoms respond and which do not respond to PPI therapy. More detailed questioning of patients often help clarify the cause for a patient’s persistent symptoms (Table 1). Atypical symptoms such as cough, chest pain, or sleep disturbance, for example, may respond poorly to PPI therapy since in this group of patients GERD is often overdiagnosed [14]. The presence of functional GI disorders should be carefully assessed because they negatively impact on the treatment of reflux symptoms [15, 16]. Patients with severe dyspeptic symptoms should be evaluated for gastroparesis. It is not uncommon that patients are initially diagnosed with GERD based on the constellation of symptoms such as hearburn and regurgitation, as well as bloating and early satiety that point to GERD as secondary to gastroparesis. In patients with refractory symptoms, one must proactively inquire about the presence of dyspeptic symptoms. The prevalence of dyspeptic symptoms is high in patients with functional heartburn [17]. Zerbib et al. have recently reported that functional dyspepsia and irritable bowel syndrome (IBS) are also strongly associated with PPI failure in patients with documented abnormal reflux [18]. Some patients may have dyspeptic symptoms that could be misinterpreted as reflux symptoms, and in this group, response to PPI is eratic at best. How IBS impacts the treatment efficacy of GERD is not exactly known, but it is hypothesised that reflux and IBS symptoms share the same underlying mechanisms (e.g., increased visceral perception) since both conditions coexist very frequently [19, 20]. The presence of psychological disorders such as hysteria, anxiety, and psychological distress should also be evaluated in patients with refractory symptoms. A systematic review of nine clinical trials reported that high levels of anxiety at baseline were associated with persistent reflux-like symptoms [21]. In short, not all that sounds like reflux may be reflux, and a high level of suspicion

Table 1. Potential causes of refractory symptoms •Not GERD - Rumination - Aerophagia - Motility disorder (achalasia) - Functional - Delayed gastric emptying - EoE (?) •Weakly acid / non-acid (less likely)

•Insufficient acid suppression - Dosing - Compliance - ZE - PPI resistance •Functional/Hypersensitivity

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Figure 1. Reractory symptoms may be from continued acid or non-acid reflux due to lack of compliance with acid-suppressive therapy or incompetent lower esophageal barrier, respectively. However, in most cases it is due to non-reflux causes.

for overlapping conditions is needed to more efficiently identify true causes for underlying symptoms. Additional common factors associated with PPI failure in patients initially diagnosed with GERD are poor compliance with medication use, obesity, and overeating (Fig. 1) [14]. Compliance for once-daily PPI in GERD is reported to be lower in patients with refractory symptoms (46–55 %) as compared to patients with adequate relief (84 %) [14]. A recent systematic review showed that compliance with medication is better in patients with severe symptoms and Barrett’s esophagus [22]. The reason for higher compliance in this group is the recognition that PPI’s help symptoms in those with true objective GERD, and when patients discontinue their therapy, symptoms recur. In addition to compliance, dosing time should also be scrutinized, since taking PPIs 15–30 min before a meal results in a better gastric pH control [23]. A recent study showed that optimal PPI dosing (before meals) occured in only 46 % of 100 patients who were referred for persistent GERD symptoms despite treatment [24]. A survey of 491 physicians found that nearly 70 % of primary care physicians and 20 % of gastroenterologists in the US advised patients to take the PPI dose at bed time or did not believe that the relationship to meals was important [25]. Therefore, any patient with refractory symptoms should be instructed regarding optimal dosing of the PPI’s. Once compliance and appropriate dosing are ensured, a single trial of a different PPI can be considered. Recent evidence from a multicenter, randomized trial showed this strategy to be helpful in some patients [26]. A randomized, controlled trial in patients with persistent GERD symptoms despite a single daily dose of PPI, showed that increasing PPI to twice daily or switching to another PPI both resulted in symptomatic improvement in roughly 20 % of patients, without a clear advantage for either strategy [27]. However, it is important to recognize that switching PPI’s will not ensure symptom control in the majority of patients presenting with refractory symptoms.

Upper gastrointestinal endoscopy Patients with persistent symptoms despite optimization of PPI therapy require further work-up. Once dosing and timing of PPI therapy is optimized, those with typical, esophageal symptoms should undergo upper endoscopy principally to exclude non-reflux esophageal disorders such as eosinophilic

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Esophagus (E Dellon, Section Editor) esophagitis (EoE), which can present with esophageal symptoms refractory to PPI, and to look for the rare patient with erosive esophagitis, a finding that provides evidence of ongoing acid reflux. Although the prevalence of EoE in patients with refractory GERD in the US has not been studied, a recent Markov model found that obtaining esophageal biopsies to diagnose EoE in refractory GERD patients is cost-effective only when the prevalence of EoE is 8 % or greater [28]. However, we can not recommend esophageal biopsies in all patients with refractory symptoms, and suggest targeting it to younger males and those with concomittant dysphagia and/or esophageal mucosa that is suspicious for EoE. If esophgeal biopsies are taken, it should be from both the distal and proximal esophagus so that reflux is not confused with EoE. Distal esophageal eosinophilia can occur in GERD alone. Endoscopy is usually of limited value since the majority of patients will have normal endoscopic findings either because they have non-GERD causes for their symptoms, they have non-erosive reflux disease (NERD), or because the use of PPIs has healed the mucosal breaks that were initially present. As an example, it is reported that only 6.7 % of patients with refractory heartburn on once-daily PPI therapy have erosive esophagitis [29]. In patients with esophagitis while on PPI therapy, other causes of esophageal inflammation must be entertained. Pill-induced esophagitis and skin diseases with esophageal involvement are other causes of PPI refractoriness and they are usually easily differentiated from peptic ulcerations located at the lower third of the esophagus [30]. The presence of mucosal breaks despite PPI therapy may reflect poorly-controlled acid reflux, which could be in some rare cases related to Zollinger-Ellison syndrome and commonly due to poor compliance or continued volume reflux due to defective antireflux barriers, especially in those with Barrett’s esophagus.

Ambulatory monitoring for reflux If endoscopy is negative, as is frequently the case, the next step is to perform reflux monitoring to quantify the degree of reflux, if any, and to establish if reflux is the underlying etiology of the patient’s continued symptoms. Reflux monitoring enables further characterization of the refractory patient, as the study may reveal: (a) PPI failure with ongoing acid reflux, which will require escalation of therapy to control acid reflux, (b) adequate acid control, but ongoing symptomatic non-acid reflux, which may respond to specific therapy, or (c) no reflux. Among refractory GERD patients with a negative reflux monitoring study, those with heartburn may be classified as having “functional heartburn” while those with extraesophageal symptoms (asthma, cough, laryngitis) will need additional or repeat work-up for non-GERD (pulmonary, allergic, ENT) etiologies. Two key issues to consider are whether reflux monitoring should be performed after stopping PPI therapy or while on medication, and what technique to use (catheter-based pH, wireless pH, or impedance-pH). At the present time, there are limited data and no clear consensus regarding the optimal testing methodology for refractory GERD. The approach to testing may be chosen based on the patient’s clinical presentation and pretest likelihood of GERD, as well as on the available technology and expertise. Reflux monitoring both off as well as on PPI offers important and clinically useful

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information. Reflux monitoring off PPI (7 days after cessation of PPI) can be performed with any of the available techniques (catheter or wireless pH, or impedance-pH). If reflux monitoring off medication is negative (normal distal esophageal acid exposure), GERD is unlikely to be the cause for a patient’s continued symptoms. In a patient with a negative test off therapy, PPI use should be discontinued and the diagnostic effort should be steered toward non-GERD etiologies. On the other hand, a positive test after PPI cessation offers objective evidence of GERD, but it does not provide insight regarding the reason for the failure to respond to treatment. Moderate to severe degree of reflux at baseline on ambulatory monitoring may be a helpful finding. A recent uncontrolled study in patients with continued symptoms despite PPI therapy suggested that the presence of a moderatelysized hiatal hernia, regurgitation, and moderate to severe acid reflux at baseline are predictors of GERD as the etiology of continued symptoms [31]. Reflux monitoring on PPI may be performed with impedance pH monitoring to enable measurement of nonacid reflux. The yield of pH monitoring alone in a patient on PPI therapy is very low because in acid-suppressed patients, reflux constituents become predominantly nonacidic [32]. In fact, pH monitoring on twice-daily PPI therapy is likely to be normal in 90–96 % of patients with refractory symptoms [33]. Although rare, an abnormal pH test in a patient taking a PPI (i.e., ongoing acid reflux despite treatment) is evidence of therapeutic failure or noncompliance. A negative pH test in treated patients makes ongoing acid reflux as the cause of their symptoms very unlikely, but it cannot account for the possibility of nonacid reflux, which can be measured using impedance-pH monitoring. A study that used the symptom index (SI) to evaluate 144 patients refractory to twice-daily PPI therapy found that ongoing symptoms were related to non-acid reflux in 37 % and acid reflux in 11 % [34]. In the remaining 52 % of patients, there was no relationship between reflux (either acid or non-acid) and symptoms. A positive SI was more common in patients with typical symptoms (heartburn, regurgitation, and chest pain) compared with those with an atypical presentation (55 % vs. 25 %). A different study using the symptom association probability (SAP) in patients who were symptomatic despite PPI therapy found a relationship between reflux and symptoms in 37 % of 60 patients; the SAP was positive due to nonacid reflux in 17 % , acid reflux in 5 % , and acid plus nonacid reflux in 15 % [35]. A systematic review that quantified acid and nonacid (both weakly acidic and weakly alkaline) reflux in studies of GERD patients on PPI therapy, found that weakly acidic reflux underlies the majority of reflux episodes in these patients and is the main cause of persistent symptoms despite PPI therapy [36]. However, there are no controlled outcome studies on the clinical relevance of non- or weakly acid reflux in patients with persistent symptoms while on PPI therapy. Finally, a negative impedance-pH test on medication strongly supports that the patient’s complaints are not due to reflux of any type. Needless to say, the full context of the patient (including clinical presentation, presence of hiatus hernia, endoscopy findings, and/or degree of response to therapy) always needs to be considered [37]. Studies comparing the yield of “off vs. on” therapy reflux monitoring in refractory GERD patients are limited. Hemmink et al. concluded that testing should be performed off PPI [38]. In contrast, Pritchett et al.

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Esophagus (E Dellon, Section Editor) Symptoms Suspected GERD Related

Warning symptoms/Signs (dysphagia/weight loss/anemia/chest pain)

(-)

(+)

Esophagogastroduodenoscopy (EGD)

Once Daily PPI Therapy (Two Months)

Response

No or Partial Response

Taper to Minimum Dose Intermittent or On-Demand Therapy Life-Style Modification (Weight Loss) EGD for Chronic Symptoms (Rule Out Barrett’s)

Response

Increase to Twice Daily PPI Ensure Proper PPI Dosing and Time

No or Partial Response EGD pH Monitoring (Off Therapy)

Moderate/Large Hiatal Hernia (> 4cm) Moderate/Severe Reflux (% time pH < 4 of > 10%)

Consider Surgical Fundoplication (especially in case of continued regurgitation)

Normal or Mild Reflux (% time pH < 4 of < 10%)

Investiage Other Causes for Symptoms (Gastroparesis, Rumination, EoE, Achalasia)

Treat for Functional Etiology (Tricyclics, Pain Modulators, SSRI’s)

Figure 2. Diagnostic and treatment algorithm for patients with symptoms suggesting GERD.

found that reflux monitoring on PPI may be the preferred strategy [39]. At present no single approach can be recommended due to the heterogeneous group of patients. A recent technical review on this topic suggested that, in the absence of high-quality studies to guide this decision, the method of testing may be chosen based upon the patient’s clinical presentation [40]. In patients with a low probability of GERD (for instance, atypical presentations without concomitant typical GERD symptoms), pH monitoring off medication may be preferred as it will enable

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ruling out GERD. Patients with a higher probability of GERD (typical symptoms, at least partial response to PPI) can be tested with impedance-pH testing on medication in search of ongoing reflux (either acid or non-acid) despite PPI. Finally, it is important to emphasize the importance of stopping PPI therapy in patients with refractory symptoms in whom all testing is negative. In a recent study, after a negative evaluation for refractory GERD that included normal endoscopy and impedance-pH monitoring, 42 % of 90 patients reported continued use of PPI despite negative results [41]. This study emphasizes the importance of educating the patient about the need to stop PPIs once GERD has been ruled out.

Esophageal manometry All patients who failed empirical management should have eosphageal manometry before reflux monitoring to position pH sensors and to rule out achalasia or severe esophageal motor disorders. Patients with achalasia are often misdiagnosed with GERD and treated with PPI’s, but continue to be symptomatic. This may be due to the overemphasis of patients on regurgitation and not dysphagia when evaluated by healthcare providers, leading to incorrect initial diagnosis as GERD. Furthermore, the prevalence of heartburn has been reported to be as high as 35 % in achalasia [30, 42]. Regurgitation with a history of aspiration pneumonia in patients without a hiatal hernia should raise suspicion for the possible diagnosis of achalasia.

Management of refractory GERD Management of patients with PPI-refractory symptoms is a common clinical challenge. An important first step is more in-depth questioning of patients about their presenting symptoms, and if GERD is still in the differential diagnosis, it is important to ensure patient compliance and appropriate dosing times with PPIs. It is also important to recognize that in most patients the cause may not be GERD at all (Fig. 1). A treatment and diagnostic algorithm is suggested in Fig. 2 for those whose initial symptoms suggests GERD as the etiology and in those who do not respond to PPI therapy.

Lifestyle modifications The specific value of lifestyle modifications in patients with refractory symptoms who have failed PPI treatment has yet to be elucidated. In a recent systematic review of publications that evaluated the value of lifestyle modifications in GERD patients, the authors determined that only weight loss and elevation of the head of the bed are effective in improving GERD [43]. However, if the patients’ symptoms are nonGERD-related, these measures will be equally uneffective. Recently, food sensitivity has been suggested to drive some of the refractory symptoms [44]. Overall, in patients with persistent symptoms despite PPI treatment, it is reasonable to recommend avoidance of specific lifestyle activities that have been identified by patients or physicians to trigger symptoms. Patients often self identify the dietary factors that result in increasing symptoms, but they may need education about reported dietary constituents that may be responsible in their continued symptoms. Dietary intervention may be especially important in those with early satiety and

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Esophagus (E Dellon, Section Editor) bloating who are suspected of having gastroparesis as the underlying etiology for their symptoms. In this group, a low-bulk and low-fat diet along with small but more frequent meals must be emphasized.

Proton pump inhibitor therapy As previously outlined, frequently applied strategies for PPI-refractory symptoms by healthcare providers are to increase the PPI dose or to change to an alternative PPI. Escalation of PPI dosing to twice daily ensures maximum control of esophageal acid exposure [33]. However, it is important to emphasize that this off-label dosing regimen should be used for a short time period (2–3 months) and should be tapered if it does not result in improvement of symptoms. There is some evidence that switching to another PPI may be cost effective and result in improvment of symptoms in some patients, [26, 27, 45] but it is not a majör strategy recommended by most experts when it comes to improving patient symptoms.

Histamine 2 receptor antagonist (H2RA) The potential effect of H2RAs on the nighttime, histamine-driven surge in gastric acid secretion previously led to the popular use of these drugs at bedtime by patients who continued to be symptomatic on a standard or double-dose PPI [46]. The addition of an H2RA at bedtime was shown to significantly reduce the duration of nocturnal acid breakthrough (NAB) [46]. Despite the lack of any clinical correlation between the presence of NAB and nocturnal GERD symptoms, the addition of H2RA at bedtime has become common practice by some providers. It is important to recognize that studies have shown no correlation between NAB and patient symptoms or esophageal acid exposure in those with refractory symptoms [47]. Additionally, there is concern about rapid tachyphylaxis developing with H2RA and, hence, their use is generally recommended in an on-demand, intermittent basis. Thus, we only recommend the use of H2RA’s in those who report nocturnal symptoms and as a substitute for the second PPI dose in those in need of additional acid suppression.

Transient lower esophageal sphincter relaxation (TLESR) reducers Drugs that can reduce the number of reflux events regardless of their acidity are theoretically desirable because of the potential for weakly acidic or bile reflux to cause symptoms. Most reflux events occur during transient lower esophageal sphincter relaxations (TLESRs). Baclofen is a GABA agonist that was first demonstrated in animals to reduce TLESR frequency without affecting the basal LES tone [48]. Indeed, baclofen at 10 mg three times daily was shown to reduce the number of TLESRs, number of reflux events, and number of symptom episodes in patients [49]. Thus, in patients with abnormal frequency of non-acid reflux, treatment with baclofen may be considered [50, 51]. Unfortunately, high-quality controlled trials are needed to demonstrate its efficacy in patients with refractory symptoms. Small, uncontrolled studies have demonstrated a benefit for baclofen when used for refractory duodeno-gastro-esophageal reflux in patients with persistent symptoms on PPI therapy [50]. On the other hand, baclofen use is limited by its significant central side-effects and relatively short half-life, which

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prompted a search for ‘cleaner’, longer-acting TLESR-inhibiting drugs with improved tolerability profiles. Arbaclofen placarbil and lesogaberan are two such drugs. Unfortunately, although they do reduce TLESR frequency, their clinical efficacy in trials was limited and both drugs have now been abandoned by their respective pharmaceutical companies [52, 53]. As a result, baclofen remains the only clinically available TLESR-inhibiting agent for patients with refractory reflux disease. If tolerated, it can be considered in patients in whom the refractory reflux symptoms appear to be caused by persistent acid or nonacid reflux on PPI therapy. However, our extensive clinical experience suggests a limited role for baclofen in patients with refractory symptoms.

Visceral pain modulators Visceral pain modulator therapy has become an attractive option for patients with refractory symptoms, particularly for those with an acid hypersensitive esophagus or functional heartburn. There is evidence that tricyclic antidepressants, trazadone, and selective serotonin reuptake inhibitors can have a beneficial effect in noncardiac chest pain. It is believed that these agents confer their visceral analgesic effect by acting at the CNS and/or peripherally at the sensory afferent level. In patients with acid-hypersensitive esophagus and refractory GERD symptoms, a randomized, placebo-controlled trial has demonstrated citalopram 20 mg/day to be of symptomatic benefit [54]. The pain modulators are used in non-mood-altering doses, and they presently provide a therapeutic alternative until more novel esophageal-specific compounds are available. Transient receptor potential vanilloid receptor 1 (TRPV1) is an acid-sensitive and heat-sensitive receptor that is proposed to transduce nociceptive reflux-induced stimuli. AZD1386 is a TRPV1 antagonist that has been shown to increase esophageal pain thresholds to heat in healthy volunteers [55]. Unfortunately, AZD1386 was shown to have no analgesic effect on esophageal pain thresholds in NERD patients with a partial response to PPI therapy [56]. Thus, at this point, tricyclic antidepressants, trazadone, and selective serotonin reuptake inhibitors are the only agents available for use in this group of patients.

Botulinum toxin injection In one recent study, botulinum toxin was administered by pyloric injection to 11 patients with refractory symptoms and associated gastroparesis [57]. Marked improvement in GERD-related symptoms was demonstrated that correlated with improvement in gastroparesis-related symptoms and gastricemptying scintigraphy. The mean duration of response was approximately 5 months [58]. However, we remain skeptical that botulinum toxin injection of pylorus would be beneficial in those with continued symptoms and no evidence of gastroparesis, since the majority of patients with refractory symptoms do not have gastroparesis.

Endoscopic therapy There are two antireflux endoscopic devices that are still currently available for human use, the Stretta procedure and the EsophyX transoral incisionless

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Esophagus (E Dellon, Section Editor) fundoplication. Some controlled studies showed clinical improvement of esophageal symptoms and decrease in PPI use with the Stretta procedure despite no significant effect on esophageal acid exposure [59–61]. Therefore, this procedure may be considered as a ‘pain modulator’ technique. However, we cannot definitively recommend its use in refractory reflux until future studies show robust responses. Transoral incisionless fundoplication using EsophyX offers a less invasive alternative to laparoscopic fundoplication that has been, as have many other endoscopic approaches, mainly evaluated in PPI-dependant GERD patients. However, two studies in patients with refractory reflux symptoms have been recently reported. A short (10 patients) prospective study showed that EsophyX normalized acid reflux parameters in only 50 % of patients (as compared with 100 % of patients with laparoscopic fundoplication), and that seven out of 10 patients had partial or no symptom remission (vs. 10/10 in the surgical group) [62]. A larger, but retrospective study in 110 patients reported a 72 % remission rate with the EsophyX procedure after a median follow-up of 7 months [63]. Therefore, the potential value of this technique should be further evaluated in controlled, prospective studies. As a result, there are no data to support the use of transoral incisionless fundoplication or other endoscopic therapy in refractory GERD at this time.

Antireflux surgery Although the failure of PPIs is one of the most common indications for antireflux surgery, it is generally considered by experts that antireflux surgery in these patients has a less favorable clinical outcome compared with that obtained in patients with adequate PPI symptom control [64, 65]. It is important to know that normal acid exposure and the presence of atypical reflux symptoms, and persisting symptoms ‘on’ PPIs are predictors of poor postoperative outcome [62]. There are some conflicting data showing favorable surgical outcomes in patients with inadequate response to PPI therapy [50, 63], however, in the absence of regurgitation as the dominant refractory symptoms, the pursuit of surgery in this group should be with caution. In the absence of proven esophagitis (i.e., the presence of mucosal breaks), it is important to document pathological reflux before considering antireflux surgery. We recommend this evaluation to be undertaken off PPI therapy to document baseline esophageal acid exposure, which is shown to be a predictor of favorable postoperative outcome, irrespective of the symptom association analysis [51, 62, 66]., Some have reported good postoperative outcomes in patients with normal esophageal acid exposure, but a positive symptom association analysis [67–69]. However, given the recent data on the lack of reliability on SI or SAP [Slaughter et al.,Kavitt et al.] we do not recommend consideration for surgery if esophageal acid expsoure is within normal ranges. Data on preoperative assessment ‘on’ PPIs are scarce. Frazzoni et al. reported good results in 38/40 patients refractory to PPIs in whom pH-impedance monitoring demonstrated either abnormal numbers of reflux episodes or positive symptom association analysis [70]. However, it must be pointed out that these patients were carefully selected and were not

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in a controlled trial. The surgical outcome of patients who have inadequate PPI control of symptoms appears to be difficult to predict. Appropriate phenotyping of patients is essential before fundoplication to exclude functional heartburn or other, non-reflux refractory symptoms (such as dyspepsia). Abnormal acid exposure time on 24-h reflux monitoring is a predictor of a more favorable postoperative outcome. In patients with abnormal acid exposure and refractory symptoms, the presence of supine acid exposure and poor esophageal motility were showen to be predictors of recurrent pathological acid exposure postfundoplication [71]. In this context, performing a reflux monitoring test ‘off’ PPI (Fig. 2) can confirm the presence of pathological reflux before surgery, and ensures the need for antireflux surgery based on objective criteria and not subjective ones such as a patient’s report of continued symptoms.

Other medical therapies The addition of antacids, alginate-based formulations such as Gavison, and sucralfate to once-daily PPI in patients with refractory GERD has yet to be studied [72, 73]. Similarly, the value of cholestyramine, a bile-acid binder, in improving symptoms of refractory GERD patients has never been assessed. However, given a short term, the use of these agents may be a reasonable approach in patients who continue to be symptomatic despite PPI therapy [74].

Alternative medicine The value of acupuncture has recently been evaluated in GERD patients who failed PPI once daily. When compared to doubling the PPI dose (standard of care), adding acupuncture was significantly better in controlling regurgitation and daytime as well as nighttime heartburn. This is the first study to suggest that alternative approaches for treating visceral pain may have a role in GERD patients with persistent heartburn despite PPI therapy [75]. However, it is not surprising that therapies that may benefit patients suffering from visceral pain might be useful in those with refractory symptoms and suspected functional etiology.

Psychological treatment Patients with poor correlation of symptoms with acid reflux events display a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid-reflux events [76]. Anxiety and depression are shown to increase GERD-like symptom reports in population-based studies. Nojkov et al. provided the first evidence that response to PPI treatment may be dependent on the level of psychological distress [77]. Thus, it is proposed that a subset of patients who did not respond to PPI therapy are more likely to have a psychosocial comorbidity than those who were successfully treated with a PPI. In these patients, treatment directed toward underlying psychosocial abnormality may improve patient response to PPI therapy. In our experience, this is an important underlying etiology in many patients with refractory symptoms without identifiable causes.

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Esophagus (E Dellon, Section Editor) In conclusion, the term “refractory GERD” should be replaced by “refractory symptoms” to avoid confusion that the underlying mechanism is reflux disease. In most patients with refractory symptoms the etiology is of non-reflux-related causes. This conclusion is based on the failure of symptoms to resolve on off-label, twice-daily dosing of proton pump inhibitor therapy after two months of therapy. The noted exception is regurgitation, which indeed could not respond to acid-suppressive therapy. In this group, a mechanical defect such as hiatal hernia is the cause and may respond better to surgical intervention. In the majority of patients with refractory symptoms, the role of ambulatory monitoring devices and endoscopy is to rule out GERD as the underlying etiology and then to focus on non-GERD-related therapies.

Compliance with Ethics Guidelines Conflict of Interest Fehmi Ates declares that he has no conflict of interest. Michael F. Vaezi has received consultancy fees and grants from Takeada. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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